The glutathione S-transferases (GSTs) are a family of Phase II detoxification enzymes that play a critical role in protecting cells for highly reactive cytotoxic agents, including carcinogens. The absence of the GSTM1 gene, a member of the n class of GSTs, in approximately half of the population has raised significant debate regarding the contribution of this enzyme deficiency to cancer susceptibility. While results from epidemiological data indicate that the GSTM1 null polymorphism confers a modest risk for cancer, in particular smoking-related cancers, these data are difficult to interpret based on the potential contribution of other genetic and environmental factors to these observations. A novel strain of 129/SvJ mice has been generated by this group in which the GSTM1 gene has been disrupted, representing the first successful attempt to recapitulate the GSTM1 gene deletion in a model system. While initial genetic characterization of F1 progeny indicated that the catalytic domain of the protein had been disrupted as anticipated, recent analyses reveal subsequent loss of the inserted antibiotic resistance marker and spontaneous rearrangement of the GSTM1 gene. Of greatest interest is the presence of lung adenomas in these aging mice, a finding consistent with the association of the GSM1 null genotype with increased risk for smoking related cancers in humans. The hypothesis of the proposed studies is that spontaneous deletion or rearrangement of the GSTM1 gene locus in GSTM1 knockout mice has increased susceptibility for cancer. In Specific Aim 1, the current structure of the GSTM1 gene locus will be characterized using fluorescence in situ hybridization and direct sequencing. The functional significance of the identified gene structure will be determined in Specific Aim 2 by comparing protein expression, mRNA expression and enzyme activity levels in heterozygous and homozygous animals. These molecular and biochemical data, when combined with the pathological assessment of homozygous animals in Specific Aim 3, will provide definitive data on the impact of loss of GSTM1 on susceptibility for cancer, in particular lung cancer. This unique mouse model provides us with the first opportunity to develop cancer preventive therapies that are tailored to this potentially high-risk target population lacking GSTM1. Public Relevance: Future assessment of the sensitivity of GSTM1-deficient mice to cancer-causing agents, especially those in tobacco smoke, will help us determine if humans carrying this genetic alteration are indeed at an increased risk of developing cancer. Based on the fact that approximately 50% of us are born without this protein (GSTM1), the impact of an effective cancer-preventive treatment for these individuals on public health could be highly significant and far-reaching.